A Phase 2 Trial of Cryosurgical Freezing and Multiplex Immunochemotherapy in Patients With Metastatic Solid Cancer
Overview
- Phase
- Phase 2
- Intervention
- Keytruda Injectable Product
- Conditions
- Metastatic Cancer
- Sponsor
- Rampart Health, L.L.C.
- Enrollment
- 32
- Locations
- 1
- Primary Endpoint
- Primary Endpoint: Efficacy
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
This study seeks to estimate the potential efficacy of the study treatment, as well as the occurrence of adverse events.
Detailed Description
Cryosurgical freezing (limited to 1.5 cm diameter single freeze within the cancer (up to two cancer sites selected and treated)) will release intact antigens to prime the immune system. The study treatment immunotherapeutic drugs (PD-1 inhibitor monoclonal antibody nivolumab or pembrolizumab and anti-CTLA-4 monoclonal antibody ipilimumab, and low-dose cyclophosphamide) will then be sequentially injected directly into each of the treated cancer sites immediately following cryosurgical freezing. These injections will be performed in combination with collagen (Helitene) to improve drug containment at the site of injection for improved local effect rather than rapid disbursement and dilution throughout adjacent interstitial spaces, as well as sustained drug delivery over time rather than a burst-release pattern. Prior to study treatment, oral low dose cyclophosphamide will be given. Post-treatment, daily subcutaneous low-dose GM-CSF injections will also be administered subsequently. It is speculated that neoantigens released from the cryoablated necrotic cancer will be available in the vicinity of the cryosurgical freezing field immediately following the procedure. Immature dendritic cells attracted to the injection site will internalize neoantigens to become activated to recognize cancer-specific antigenic proteins. The activated dendritic cells will recruit killer T-cells to the injection site to attack cancer cells, and then migrate through the lymphatic system to sites of metastases, targeting cancer-specific neoantigens and recruiting more killer T-lymphocytes to destroy other cancer cells harboring the precise antigenic epitopes (abscopal (bystander) effect). In this way, dendritic cells are capable of initiating cell-mediated systemic immune response in combination with cytotoxic killer T-cells. Regulatory T lymphocytes, which have been implicated in dampening or halting cell-mediated, antigen-specific immune responses, will be selectively depleted by anti-CTLA-4 monoclonal antibodies, low-dose cyclophosphamide, and metronomic GM-CSF. Intra-tumoral injection of the immunotherapeutic medications assists in stimulating and harnessing the local and systemic immune response. GM-CSF prolongs the immune response. Using this combination of therapies, referred to as AbscopalRx5001, it is thought that a clinically significant systemic anti-cancer immune response might be elicited. Intra-tumoral injection of drugs will likely offer fewer side effects than systemic therapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Be willing and able to provide written informed consent/assent for the trial.
- •Be ≥18 years of age on day of signing informed consent.
- •Have a performance status of 0-3 on the ECOG Performance Scale.
- •Have a life expectancy of 6 months or more as determined by treating physician.
- •Have exhausted all other standard therapies; Have failed available therapy or are not a candidate for, or refuse available therapy (i.e. concerned with high adverse events rate in available therapy or outcome worse than disease); or failure of prior chemotherapy.
- •Histologically-documented solid cancer. All subjects must submit their primary tumor or metastatic pathology specimens and laboratory and imaging reports to Rampart Health where they will be centrally reviewed. Central Rampart Health pathologic review is not required for screening but rather for confirmation of diagnosis and histologic subtype of cancer. Local pathologic review is sufficient for eligibility determination.
- •Measurable disease as defined using iRECIST criteria and identified by radiographic imaging (Imaging should be current within the past three months of subject entering the study; if not repeat imaging must be done prior to enrollment.). In order to be eligible, the patient must have at least one metastatic bone and/or metastatic soft tissue site, lymph node site, and/or bone site with cancer mass measuring 1.0 cm or more in diameter based on soft tissue, lymph node, and/or bone lesions as defined by any of the following:
- •Any soft tissue lesion defined by imaging deemed by the physician to be consistent with distant metastatic disease. For patients undergoing PSMA PET (prostate cancer patients only), only PSMA avid lesions that have a CT or MRI correlate consistent with metastasis will be counted as a site of metastasis.
- •Metastatic lymph node disease defined by imaging. Any lymph node ≥ 1.5 cm in shortest dimension will be noted as involved with disease.
- •Bone metastases defined by bone imaging. If the patient has technetium bone scan and/or NaF PET performed, either study may be used for documenting metastases; both scans do not need to show the number of metastases required for study entry. For patients undergoing PSMA PET (prostate cancer patients only), only PSMA-avid lesions that are consistent with metastasis will be counted as a site of metastasis.
Exclusion Criteria
- •Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
- •Has bone metastasis as the only site of disease.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of trial treatment, with the exception of steroids for adrenal insufficiency in which case prednisone \<10mg/day or its equivalent is allowed.
- •Has a performance status of 4-5 on the ECOG Performance Scale.
- •Has a known history of active TB (Bacillus Tuberculosis).
- •Hypersensitivity to monoclonal antibodies such as nivolumab (or pembrolizumab) or any of its excipients.
- •Has had a prior anti-cancer monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •Is taking any current medication known to interfere with serum PSA concentration or radiographic extent of cancer (e.g., Enzalutamide, hormonal therapy) within 30 days for non-depot or 90 days for depot of start of treatment.
- •Clinically significant (i.e. active) cardiovascular disease: cerebral vascular accident (\<6 months prior to enrollment), myocardial infarction (\<6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Persisting toxicity related to prior therapy (NCI CTCAE v.5 Grade \> 1); however, alopecia, sensory neuropathy Grade ≤ 2, Grade 2 anemia, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
Arms & Interventions
Single arm. Subjects receiving treatment.
Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by overall response rate of radiographic changes according to iRECIST criteria.
Intervention: Keytruda Injectable Product
Single arm. Subjects receiving treatment.
Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by overall response rate of radiographic changes according to iRECIST criteria.
Intervention: Yervoy Injectable Product
Single arm. Subjects receiving treatment.
Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by overall response rate of radiographic changes according to iRECIST criteria.
Intervention: Cytoxan
Single arm. Subjects receiving treatment.
Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by overall response rate of radiographic changes according to iRECIST criteria.
Intervention: Cryosurgical freezing (cryosurgery)
Single arm. Subjects receiving treatment.
Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by overall response rate of radiographic changes according to iRECIST criteria.
Intervention: GM-CSF Injectable
Outcomes
Primary Outcomes
Primary Endpoint: Efficacy
Time Frame: baseline to 8 weeks after end of treatment (approximately 5 months))
Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by overall response rate of radiographic changes according to iRECIST criteria.
Secondary Outcomes
- Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy(baseline to 8 weeks after end of treatment (approximately 5 months);)